Project Summary Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and ultimately fatal disorder for which two anti- fibrotic drugs, have recently been approved. Unfortunately, neither drug is curative While clinical trials have demonstrated that both drugs slow the rate of decline in lung function, responses are variable and side effects lead to discontinuation of drug treatment in up to 40% of patients in the first year. IPF therefore remains a chronic, fatal disease driving down quality of life and driving up health care utilization and costs. More effective therapies that will safely and effectively modify the course of IPF and restore quality of life are urgently needed. Dr. Joel Dudley and his team have used a data-driven approach to identify a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a Phase 2-ready Src kinase in- hibitor. With this in silico data, Dr. Dudley has partnered with Drs. Gregory Downey (National Jewish Health) and Naftali Kaminski (Yale University) to validate and bring these findings to clinical application. Drs. Downey and Kaminski are each leaders in translational research and clinical care for IPF patients. Based on the tran- scriptomic findings, published literature, and preliminary evidence in the bleomycin preclinical model of this disease, we hypothesize that saracatinib, a Src kinase inhibitor, represents a new, targeted, more effective, and safer therapy for IPF than existing medications. In the UG3 segment of this proposal, we will examine the ability of saracatinib to perturb candidate biomarkers relevant to IPF pathogenesis. Computational analysis will be used to overlay the PBMC signature associated with poor prognosis in IPF, the IPF disease signature, and the saracatinib drug signature to identify candidate biomarkers for further study. These biomarkers will then be experimentally tested in preclinical in vitro and in vivo models. The key milestone for the UG3 to UH3 transition is identification of a panel of biomarkers associated with rapid IPF progression and saracatinib activity to sup- port the clinical study. These data will be rapidly integrated into a clinical study (UH3) designed to establish proof of concept and mechanism data in IPF patients. Full pharmacology and safety data are available to sup- port long-term administration of saracatinib with a favorable tolerability profile and potential for rapid translation into the clinic. The UH3 segment comprises a biomarker-based, adaptive design, integrated Phase 1b/2a trial of saracatinib in newly diagnosed IPF patients (100 patients total; 50 drug and 50 control) with an interim anal- ysis to check the biomarkers after the first 15 subjects reach 4 weeks and 12 weeks of treatment and adapt the design as necessary from that point (e.g. increase sample size or change drug dose). The primary endpoint for the trial will be change in the risk ratio (based on the 52-gene signature in blood leukocytes). The secondary end points will include change in HRCT chest scan quantification of fibrosis; slope of FVC; DLCO; 6-minute walk test; additional serum biomarkers including KL-6, MMP-7, osteopontin, collagen peptides, and additional serum biomarkers identified in the UG3; time to the first acute exacerbation, and quality of life questionnaires.